Medicinal agent



Patented Jan. 2, 1940 4 UNITED STATES 2,185,824 .manicmar. AGENT Gordon A. Alles, Loo Angeies, Calif.

No Drawing.

Original application September 16, 1938, Serial No. 230,205.

Divided and this application October 21, 1939, Serial No. 300,662

40iaims.

This invention relates to a medicinal agent having various uses in therapeutic treatment of animals and man.

The principal object of the invention is to 5 provide a new and useful medicinal agent.

The new medicinal agent in accordance with this invention will be found to have various medical uses, and from the standpoint of its therapeutic characteristics, will be found eiiective for various purposes and particularly for ad- 1 ministration to mucosal membranes to stimulate peripheral neuro-muscular mechanisms under the control of the sympathetic nervous system.

The medicinal agent in accordance with this invention may be employed in various forms and may be variously administered. Thus, for example, it may be used in liquid solution, or in solid form such as in-powder or tablets, alone or with other ingredients as desired, and it may so be variously administered, for example, by mouth or rectally for application to the mucosal membrane comprising the gastro-intestinal tract, or it may be locally administered to other mucosal membranes as, for example, the nasal mucosa and the conjunctiva of the eye bytampon, dropper or spray.

Broadly speaking, the new medicinal agent in accordance with this invention comprises the stable, soluble non-toxic addition salts of 1- (parahydroxyphenyl)-2-aminopropane, as, for.

example, the hydrochloride, hydrobromide, hy-

drosuliate, hydrogen acid tartrate, and the like.

The compound aminopropane was described in the German 35 Patent No. 243,546, issued February 13, 1912,

as having therapeutic properties closely similar to those of l-(parahydroxyphenyl) -2-aminoethane. This, latter drug compound has been well established to exert a stimulant action upon 40 body functions that are activated by the sympathetic nervous system, but its eflects as with many related compounds, are only evident when the drug is introduced parenterally.

In my studies, I have iound that the administration of 20, 50, 100 or even 200 milligrams oi 1-(parahydroxyphenyD-2-aminoethane hydrochloride by'mouth to man was not eflective in causing a change inblood pressure, which would result from stimulation of the sympathetic nervous system of the blood vessels and heart.

However, the oral administration-of but 20 milligrams of l-(parahydroxyphenyl) -2-aminopropane hydrochloride to man was usually effective in causing a definite rise in blood pressure acr-z 's companied oiten by an evident change in heart I-(parahydroxyphenyl) -2 rate. The oral administration of as much as 50 milligrams of the same compound to man was regularly effective, in causing a marked rise in blood pressure that oiten exceeded the normal level by 50 or more millimeters of mercury pressure, and in causing a marked change in heart rate. The following tables are further illustra tive oi the comparative efiect of these two compounds on blood pressure when applied to the mucosal membrane comprising the gastro-in- 10 testinal tract:

Table I Milligrams ol 1- (parahydroxyphenyl -2- aminoethane taken orally 15 20mg. mg. 100 mg. 200mg.

mun values before I 110/70-64 112/68-62 114 6-70 112 72-72 gfffff moles-c0 112170-60 110/36-72 nzn-u Ammo 1111mm--." 108/68-62 2 112/76-70 114/68-74 Altai-maximizes.-. 104/88-62 112/70-56 0/74-66 118/66-74 Aiter30minutes- 106/68-62 114/72-56 110/74-66 114/68-76 Amrmminutesfl- 102/70-60 2/70-58 112/76-66 112/66-74 Ami-commutes--- 106/70-58 112/70-64 112/76-70 112/7044 60mlnum [-58 112/72-54 112/76-66 112/70-70 Aitcrminutes. 1 no-sc /72-62 110 74-62 110/66-70 25 Amnoo 1111111368---. 110/74-56 112/72-52 110/72-66 112/74-66 After no 1111111368.... 106/74-66 110170-52 112/74-64 112/74-66 Table II 30 Milligrams of l-(parahydroxyphenyl) 2 aminopropane taken orally 20 mg. 50 mg. 35

Initial values before taking drug com- 114 6-60 l06/66-60 Alter mini:

Other stable acid addition salts such as the hydrobromide, the hydrosulfate and the hydrogen acid tartrate are equivalently effective with the 50 hydrochloride. g

A study of the pharmacological activity of the stable, soluble non-toxic salts of 1- (parahydroxyphenyl) -2-aminopropane has shown that, when applied directly to mucosal membranes, they 55 will be found to be stimulating to peripheral neuro-muscular mechanisms under the control of the sympathetic nervous system. This stimulation results in various physiological and therapeutically useful effects, other than its pressor action as detailed ante, such as, for example, dilatation of constricted bronchial muscles such as are responsible for asthmatic attacks, the production of mydriasis, making it of particular use in refraction, vasoconstriction of the nasal mucosa, etc. If desired, general systemic stimulation may be produced by bringing the medicinal agent contemplated by this invention into contact with the gastro-intestinal mucosa through oral or rectal administration. Localized action may be obtained by topical application to other mucosal surfaces such as the eye ornose.

The medicinal agents contemplated by this invention may be readily prepared according to well known procedure. Thus, for example, the base, 1- (parahydroxyphenyl) -2-aminopropane, is first prepared, for example, by hydrolysis and demethylation of l-(paramethoxyphenyl) -2- formylaminopropane which, in turn, may be prepared, for example, by methods fully desribed in United States Patent No. 2,011,790, issued to me on August 20, 1935. The stable, soluble nontoxic acid addition salts are then readily prepared, for example, from a solution ofthe base in a suitable solvent by neutralization with an acid corresponding to the particular salt desired and crystallization of the salt from solution.

In using the broad and specific embodiments of this invention as a medicinal agent, the desired salt of l-(parahydroxyphenyl) -2-aminopropane may be orally or rectally administered in solid tabletted form suitably extended by association with an excipient such as lactose, starch, etc. or in aqueous or alcoholic solutions. For local application to other mucosal surfaces such as the nose to produce vasoconstriction or to the conjunctiva to produce mydriasis, solutions of the salts may be employed.

The nature and proportions of other ingredients that may be used, as' excipients, with the salts comprising the'medicinal agent, are sub- J'ect'to wide variation, according to the therapeutic effect to be attained and the method in which the preparation is to be administered. Thus the proportion of the salts to the excipients may be as low as 1% or even less whenused in solution, or as much as 50% or even as high as 90% in other cases, for example, as when used in solid tabletted form. While the salts may be used undiluted, an excipient of some sort is usually preferable to impart other desired physical properties, such as, for example, bulk, perfume, color or the like. Thus a medicinal agent in accordance with this invention may comprise the salts, alone or together with a suitable excipient.

By way of illustration, for example, tablets for oral administration are prepared by mixing one part of a stable, soluble, non-toxic acid addition salt of l-(parahydroxyphenyl)-2-aminopropane with nine parts of lactose, or similar excipient and compressing into tablets weighing 200 or 500 milligrams each. Flavoring or coating of such tablets may be provided if desired.

Aqueous solutions for topical application to eye or nasal membranes are prepared by dissolving 1.0g. l-(parahydroxyphenyl) -2-aminopropane hydrobromide in 100 cc. of water saturated with boric acid, this water solution serving as an effective extender for the therapeutically active salt.

Elixirs for oral administration of the salts of the base are well prepared by dissolving 5 g. of the desired salt in 100 cc. of water and adding 125 cc. ethanol, cc. of lemon flavor concentrate and 765 cc. of 60% simple sucrose syrup, which may be tinted with a certified dyestufi.

The advantages of oral administration of medicinal agents employed in the treatment of a chronic difiiculty are obvious. Previous administration of agents of the character at present involved has been substantially confined to hypodermic, injection subcutaneously, intramuscularly, or intravenously, which provides more direct introduction into the blood stream. Such administration is clearly unsuited to self-treatment, in view of the difiiculties interposed with respect to obtaining sterile conditions. Furthermore, the continuous use of hypodermic injections is well-known ,to have a deleterious local effect upon body tissues. On the other hand, the medicinal agents of the character herein described may be self-administered without difiiculty and without danger of infection, and without the deleterious effects attendant upon continued use of hypodermic injections.

This application is adivision of the application filed by me September 16, 1938, Serial No. 230,205, which application was filed by me as a continuation-in-part ofthe application filed by me July 13, 1935, Serial No. 31,279.

What I claim and desire to protect by Letters Patent is:

1. A medicinal agent for administration by application to mucosal membranes to stimulate peripheral neuro-muscular mechanisms under control of the sympathetic nervous system, comprising 1 -(parahydroxyphenyl) 2 -aminopropane hydrogen acid tartrate suitably extended by association with an excipient adapting it for application to mucosal membranes.

2. A medicinal remedy for administration by introduction into the gastro-intestinal tract to stimulate peripheral neuro-muscular mechanisms under the control of the sympathetic nervous system comprising 1-(parahydroxyphenyD-2-aminopropane hydrogen acid tartrate in a form for oral administration.

3. A medicinal agent for administration by application to the conjunctival mucosa to stimulate peripheral neuro-muscular mechanisms under control of the sympathetic nervous system, comprising 1- (parahydroxyphenyl) -2-.aminopropane hydrogen acid tartrate suitably extended by association with an excipient adapting it for application to the conjunctival mucosa.

4. A medicinal agent for administration by application to the nasal mucosa to stimulate peripheral neuro-muscular mechanisms under control of the sympathetic nervous system compris-" ing 1 -(parahydroxyphenyl) 2 -aminopropane hydrogen acid tartrate suitably extended by association with an excipient adapting it for application to the nasal mucosa.

GORDON A. ALLES. 

